title: Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin.
abstract: OBJECTIVE
  Diabetes mellitus is associated with metabolic bone disease and increased low-impact fractures. The insulin-sensitizer metformin possesses in vitro, in vivo and ex vivo osteogenic effects, although this has not been adequately studied in the context of diabetes. We evaluated the effect of insulin-deficient diabetes and/or metformin on bone microarchitecture, on osteogenic potential of bone marrow progenitor cells (BMPC) and possible mechanisms involved.
  
  
  METHODS
  Partially insulin-deficient diabetes was induced in rats by nicotinamide/streptozotocin-injection, with or without oral metformin treatment. Femoral metaphysis micro-architecture, ex vivo osteogenic potential of BMPC, and BMPC expression of Runx-2, PPARγ and receptor for advanced glycation endproducts (RAGE) were investigated.
  
  
  RESULTS
  Histomorphometric analysis of diabetic femoral metaphysis demonstrated a slight decrease in trabecular area and a significant reduction in osteocyte density, growth plate height and TRAP (tartrate-resistant acid phosphatase) activity in the primary spongiosa. BMPC obtained from diabetic animals showed a reduction in Runx-2/PPARγ ratio and in their osteogenic potential, and an increase in RAGE expression. Metformin treatment prevented the diabetes-induced alterations in bone micro-architecture and BMPC osteogenic potential.
  
  
  CONCLUSIONS
  Partially insulin-deficient diabetes induces deleterious effects on long-bone micro-architecture that are associated with a decrease in BMPC osteogenic potential, which could be mediated by a decrease in their Runx-2/PPARγ ratio and up-regulation of RAGE. These diabetes-induced alterations can be totally or partially prevented by oral administration of metformin.
authors.affiliation: Laboratorio de Investigación en Osteopatías y Metabolismo Mineral, Department of Biological Sciences, School of Exact Sciences, National University of La Plata, Argentina.
authors.forename: María José
authors.initials: MJ
authors.lastname: Tolosa
authors.forename: Sara Rocío
authors.initials: SR
authors.lastname: Chuguransky
authors.forename: Claudia
authors.initials: C
authors.lastname: Sedlinsky
authors.forename: León
authors.initials: L
authors.lastname: Schurman
authors.forename: Antonio Desmond
authors.initials: AD
authors.lastname: McCarthy
authors.forename: María Silvina
authors.initials: MS
authors.lastname: Molinuevo
authors.forename: Ana María
authors.initials: AM
authors.lastname: Cortizo
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology*; D007328:Insulin / Q000172:deficiency*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
chemical_list: D007328:Insulin; D008687:Metformin
keywords: Bone marrow progenitor cells; Bone microarchitecture; Diabetes mellitus; Metformin